Molecular targeting of proteins by L-homocysteine: mechanistic implications for vascular disease.

Abstract:

:Hyperhomocysteinemia is an independent risk factor for cardiovascular disease, complications of pregnancy, cognitive impairment, and osteoporosis. That elevated homocysteine leads to vascular dysfunction may be the linking factor between these apparently unrelated pathologies. Although a growing body of evidence suggests that homocysteine plays a causal role in atherogenesis, specific mechanisms to explain the underlying pathogenesis have remained elusive. This review focuses on chemistry unique to the homocysteine molecule to explain its inherent cytotoxicity. Thus, the high pKa of the sulfhydryl group (pKa, 10.0) of homocysteine underlies its ability to form stable disulfide bonds with protein cysteine residues, and in the process, alters or impairs the function of the protein. Studies in this laboratory have identified albumin, fibronectin, transthyretin, and metallothionein as targets for homocysteinylation. In the case of albumin, the mechanism of targeting has been elucidated. Homocysteinylation of the cysteine residues of fibronectin impairs its ability to bind to fibrin. Homocysteinylation of the cysteine residues of metallothionein disrupts zinc binding by the protein and abrogates inherent superoxide dismutase activity. Thus, S-homocysteinylation of protein cysteine residues may explain mechanistically the cytotoxicity of elevated L-homocysteine.

journal_name

Antioxid Redox Signal

authors

Glushchenko AV,Jacobsen DW

doi

10.1089/ars.2007.1809

subject

Has Abstract

pub_date

2007-11-01 00:00:00

pages

1883-98

issue

11

eissn

1523-0864

issn

1557-7716

journal_volume

9

pub_type

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